1. Field of the Invention
The present invention relates generally to immunoconjugates and, more particularly, to hepatic and reticuloendothelial blocking agents useful in the enhancement of the bioavailability of therapeutic and diagnostic immunoconjugates.
The advent in 1975 of hybridoma technology and subsequent monoclonal antibody (MoAb) production spawned an entire industry devoted to the development of MoAb-based products. The property of MoAbs of greatest interest is their ability to bind antigenic determinants or epitopes of predefined specificity. This property has led the news media to describe MoAbs as "magic bullets."
Founded on the theory of employing MoAbs as targeting agents for the cell-specific delivery of therapeutic or diagnostic moieties, much of the art has been concerned with the development of compositions known as immunoconjugates. These compositions are created by forming a molecular bond between a therapeutic or diagnostic moiety and a MoAb or an active binding fragment thereof Such conjugates are useful in the diagnosis and treatment of a variety of medical conditions, not the least of which being cancer in many of its forms.
As promising as immunoconjugates appear, they nonetheless share a common problem associated with the administration of any drug to an animal or a human; the problem of bioavailability or biodistribution. That is, the drug or agent must be made available to the target cells in a useful form and in an efficacious concentration. Clinicians constantly battle with the mammalian body's remarkable ability to rapidly clear drugs via the liver, kidneys and other organs. While a variety of compositions have been tested with respect to enhancing the biodistribution of drugs such as, for example, chemotherapeutic agents, efficacy of these compositions with respect to immunoconjugates is largely unproven. There is therefore a need for methods and compositions proven useful in enhancing the biodistribution of immunoconjugates.
2. Description of the Relevant Literature
Stahl and Schlesinger, TIBS (July 1980) - :194-196, discuss recognition and clearance of certain substances terminating in mannose which have short plasma survival times mediated via receptors on Kupffer cells and macrophages.
Simmons, et al., J. Biol. Chem. (June 1986) 261:7912-7920, describe mannose receptor uptake of ricin and RTA by macrophages, and show that removal of carbohydrate from ricin decreases uptake and toxicity.
Ponpipom et al., J. Med. Chem. (1981) 24:1388-1395 describe D-mannosyl peptide analogues (including Man.sub.3 Ly.sub.2) which block uptake of labeled D-mannose-bovine serum albumin by rat alveolar macrophages.
Bourrie, et al., Eur. J. Biochem. (1986) 155:1-10, report on rapid clearance of an immunotoxin due to recognition of RTA mannose residues by liver cells, and enhancement of levels of immunotoxin in circulation by the coadministration of yeast mannan which inhibits liver uptake.
Skilleter and Foxwell, FEBS Letters (1986) 196:344-348, discuss inhibition of liver cell uptake of ricin A chain using D-mannose, L-fucose or ovalbumin.
Ashwell and Morell, "The role of surface carbohydrates in the hepatic recognition and transport of circulating glyco proteins." In Advances In Enzymology and Related Areas of Molecular Biology, Vol. 41 (A. Meister, ed.), p. 99-128. New York: Interscience Publication, a division of John Wiley and Sons, 1974, provide an overview of hepatic recognition of circulating glycoproteins via their surface carbohydrates.
Shen. T., "Cell surface receptors." In Directed Drug Delivery, A Multidisciplinary Problem, (R. Borchardt, A. Repta, and V. Stella (eds.), p. 231-45. Clifton, N.J.: Humana Press, 1985, discusses the uptake of mannosyl-lysine via receptors on Kupffer cells.